The metabotropic glutamate receptors (mGluRs) have attracted considerable interest as novel therapeutic targets for multiple neurological and psychiatric conditions. Among the least studied of the eight subtypes of the mGluR family is mGluR3, where selective ligands have yet to be identified. In spite of this limitation, we have made significant progress in elucidating the roles and functions attributable to mGluR3, including a novel role for mGluR3 in regulating hippocampal function. Specifically, we have shown that group II mGluRs (mGluR2 and mGluR3) participate in a novel form of glial-neuronal communication in the hippocampus in which activation of mGluRs on astrocytes leads to release of adenosine and reduction of glutamate release from neighboring glutamate synapses. We postulate that this astrocytic response is mediated by the mGluR3 subtype and that activation of mGluR3 could impair hippocampal LTP. These results lead us to hypothesize that selective antagonists of mGluR3 could have cognition-enhancing effects. Prior studies with mGluR2/3 antagonists using both wild-type and mGluR2 knockout mice in the Morris water maze, a model of spatial learning that depends on normal hippocampal function, are consistent with mGluR3 functioning as the predominant group II mGluR subtype responsible for the cognition-enhancing effects seen with group II mGluR antagonists. Additionally, exciting new preclinical studies reveal that group II antagonists have robust efficacy in multiple animal models that predict antidepressant activity. Highly selective antagonists that are suitable for use in animal models are needed in order to better understand the respective roles of mGluR2 and mGluR3 in these studies. In addition to our multiple series of group II mGluR antagonists, we have recently discovered a series of compounds that are selective antagonists of mGluR3. Importantly, these new selective antagonists are from a chemotype that has previously delivered efficacious CNS tool compounds in the past. These selective compounds offer an unprecedented opportunity to systematically test the hypotheses presented above. In order to accomplish our goals we will optimize our compounds such that the resultant probe will possess the balance of properties required to make it a highly valuable tool to the research community. The optimization process will involve an iterative medicinal chemistry library approach focused not only on potency and selectivity, but a number of DMPK parameters associated with CNS exposure. Using our selective antagonists of mGluR3, along with mGluR3 knockout mice, we plan to rigorously test the hypothesis that blockade of mGluR3 inhibits group II mGluR-mediated astrocytic-neuronal communication in hippocampal area CA1. In addition, we will test the hypothesis that coactivation of mGluR3 and bARs leads to an impairment of hippocampal LTP. Finally, we will examine our optimized compounds in efficacy models where mGluR2/3 antagonists have been shown to have cognition-enhancing and antidepressant-like effects in order to elucidate the respective roles of each receptor. PUBLIC HEALTH RELEVANCE: Recent studies suggest that drugs that selectively block actions of a specific neurotransmitter receptor, termed mGluR3, may provide a novel approach for treatment of major depression and may improve memory formation in patients suffering from serious brain disorders. We have discovered new molecules within a chemotype proven to deliver efficacious CNS tool compounds that selectively inhibit this neurotransmitter receptor. Studies are proposed to optimize the properties of these molecules through iterative medicinal chemistry so that they can be used to test the hypothesis that mGluR3 inhibitors have actions that predict efficacy in treatment of depression and cognitive impairments.